Details

Autor(en) / Beteiligte

• Yamazaki, Satoko
• Tan, Lu
• Mayer, Günter
• Hartig, Jörg S.
• Song, Jin-Na
• Reuter, Sandra
• Restle, Tobias
• Laufer, Sandra D.
• Grohmann, Dina
• Kräusslich, Hans-Georg
• Bajorath, Jürgen
• Famulok, Michael

Titel

Aptamer Displacement Identifies Alternative Small-Molecule Target Sites that Escape Viral Resistance

Ist Teil von

• Chemistry & biology, 2007-07, Vol.14 (7), p.804-812

Ort / Verlag

United States: Elsevier Ltd

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• Aptamers targeting reverse transcriptase (RT) from HIV-1 inhibit viral replication in vitro, presumably by competing with binding of the primer/template complex. This site is not targeted by the currently available small-molecule anti-HIV-1 RT inhibitors. We have identified SY-3E4, a small-molecule inhibitor of HIV-1 RT, by applying a screening assay that utilizes a reporter-ribozyme regulated by the anti-HIV-1 RT aptamer. SY-3E4 displaces the aptamer from the protein, selectively inhibits DNA-dependent, but not RNA-dependent, polymerase activity, and inhibits the replication of both the wild-type virus and a multidrug-resistant strain. Analysis of available structural data of HIV-1 and HIV-2 RTs rationalizes many of the observed characteristics of the inhibitory profiles of SY-3E4 and the aptamer and suggests a previously not considered region in these RTs as a target for antiviral therapy. Our study reveals unexplored ways for rapidly identifying alternative small-molecule target sites in proteins and illustrates strategies for overcoming resistance-conferring mutations with small molecules.